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Reconstructing Mammalian Retinal Tissue ISSN: 2469-570X Rieke et al. Int J Stem Cell Res Ther 2018, 5:051 DOI: 10.23937/2469-570X/1410051 Volume 5 | Issue 1 International Journal of Open Access Stem Cell Research & Therapy ORiGinAL ReseARch Reconstructing Mammalian Retinal Tissue: Wnt3a Regulates Lam- inar Polarity in Retinal Spheroids from Neonatal Mongolian Rats, while RPE Promotes Cell Differentiation Matthias Rieke, Afrim Bytyqi, Florian Frohns and Paul G Layer* Check for Entwicklungsbiologie & Neurogenetik, Technische Universität Darmstadt, Germany updates *Corresponding author: Dr. Paul G Layer, Professor, Entwicklungsbiologie & Neurogenetik, Technische Universität Darm- stadt, Schnittspahnstrasse 13, D-64287 Darmstadt, Germany, Tel: +6151-1624610, E-mail: [email protected] Abstract Abbreviations Besides invention of iPSC technology, recent progress of ACs: Amacrine Cells; AChE: Acetylcholinesterase; AM: Ag- stem cell-based organoids is founded on long-standing gregation Medium; ATC: Acetylthiocholine; CMZ: Ciliary Mar- 3D-reaggregate approaches from embryonic tissues. In ginal Zone; CM: Conditioned Medium; CR: Calretinin; dACs: particular, histotypic in vitro reconstruction of avian retinal Displaced Amacrine Cells; DAPI: 4’,6-diamidine-2-phenylin- spheroids was most prolific. For instance, a complete re- dole-dihydrochloride; div: Days In Vitro; DKK: Dickkopf; E: Em- constitution of all retinal layers was possible, which was bryonic Day; Fzd: Frizzled; GCL: Ganglion Cell Layer; GCs: supported by Wnt signalling and factors from the retinal Ganglion Cells; i.c.: In Culture; INL: Inner Nuclear Layer; IPL: pigmented epithelium (RPE); similar in vitro findings are Inner Plexiform Layer; HCs: Horizontal Cells; nbl: Neuroblastic still missing for mammals. Using an established model of Layer; ONL: Outer Nuclear Layer; OPL: Outer Plexiform Layer; reaggregates from dispersed retinal cells of the neonatal P: Postnatal Day; PR: Photoreceptor; RPE: Retinal Pigmented Gerbil [1], we show here that in contrast to supernatant Epithelium from RPE (RPE ), supplementation with Wnt3a induced CM Note: retinal layers in spheroids are denoted in lower-case let- a correct inside-out polarity of retinal layers. XAP1+ precur- ters, indicating that these are layers homologous, but not iden- sors of photoreceptors (PRs) were correctly found on the tical, to the in vivo retina. external face of the sphere, but general cell differentiation remained limited. If Wnt3a was present for 4 days in vitro (div) only, the correctly polarized tissue further differentiat- Introduction ed, e.g., more calretinin+ amacrine cells (CR+ ACs) sent out processes into an ipl-like layer and rhodopsin expression of Tremendous progress has been made towards in vi- PRs became detectable. Finally, if Wnt3a during 4 div was tro production of human organo-typic tissues, so-called followed by RPE treatment, all retinal layers with most cell CM organoids [2-5], since induced pluripotent stem cells types were arranged in correct order, as shown by markers including CR, Pax6, AChE, PKCá, CRALBP, and Cern901. (iPSCs) have become available from adult human tis- LiCl experiments showed that the canonical Wnt/β-catenin sues [6]. The possible applications of brain organoids, pathway was involved. We conclude that Wnt3a conveyed including retina, are widespread in transplantation a correct inside-out laminar polarity but kept cells in an un- medicine and pharmaceutical testing [7]. Besides the differentiated state, while RPECM strongly promoted retinal differentiation. Both together supported a nearly complete invention of iPSC production, organoid technologies retinal tissue reconstruction from fully dispersed cells, as are based on long-standing methods of histotypic reag- never achieved before for cells from any mammalian retina. gregation of embryonic stem cells from various tissue/ organ origins. Reaggregation of completely dispersed Keywords retinal cells under constant rotation, and their differen- Gerbil, Inner plexiform layer, Meriones unguiculatus, Reti- tiation into 3-dimensional histotypic retinal cell spheres nal spheroids, Retina tissue engineering, Retinal pigmented (called retinal spheroids, or retino-spheroids) allow to epithelium Citation: Rieke M, Bytyqi A, Frohns F, Layer PG (2018) Reconstructing Mammalian Retinal Tissue: Wnt3a Regulates Laminar Polarity in Retinal Spheroids from Neonatal Mongolian Rats, while RPE Promotes Cell Differentiation. Int J Stem Cell Res Ther 5:051. doi.org/10.23937/2469-570X/1410051 Received: February 27, 2018: Accepted: April 23, 2018: Published: April 25, 2018 Copyright: © 2018 Rieke M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Rieke et al. Int J Stem Cell Res Ther 2018, 5:051 • Page 1 of 11 • DOI: 10.23937/2469-570X/1410051 ISSN: 2469-570X analyse tissue construction in a “cell-by-cell” manner, can strongly affect the acquisition of peripheral retinal and thus helps to develop rationales for the production characteristics both in chick and mouse [21,23]. Never- of complete retinal tissues from appropriate embryon- theless, several studies have suggested that for neural ic or adult stem cells. Following primary reaggregation retina development the canonical β-catenin pathway and sorting out of cells, periods of proliferation and dif- could be of minor significance. For mouse, Wnt/β-cat- ferentiation of cells, and their correct integration into enin signalling was associated with a non-canonical role a 3D-tissue environment are formative. In fact, reag- [14]. Thereby, β-catenin activation was not affecting gregation of retinal and RPE cells from chicken embry- neurogenesis but rather retinal lamination, possibly by os represented the most amenable and yielding model its functioning in cell adhesion [24]. (reviewed in [8-10]). A first complete laminar retinal In chick, the addition of Wnt2b to retinal reaggre- organisation has been achieved by mixing dissociated gates had induced their complete laminar organization retinal pigmented epithelial (RPE) with retinal cells from [25], similar to what we had achieved in the avian sys- the 5-6 days-old chicken embryo [11]. This model has tem under the influence of supernatants from RPE or allowed to analyse minute steps of retinalin vitro tissue Müller cells [9,26-28]. Therefore, we here i) Not only formation (see Discussion); in fact, it let us predict the found ways to produce laminar retinal spheroids from present progress in human regenerative medicine [8- an embryonic mammal, but ii) Analysed the role(s) of 10]. Until now, comparable histo-formative insights into Wnt3a in Gerbil retinal spheres, and correlated them differentiation of human retinal organoids from iPSCs with the effects of RPECM. Expecting that both factors, have not yet been achieved. Wnt3a and RPE, should exert similar effects, we found to Thus clearly, a detailed knowledge derived from the contrary that Wnt3a conveys the correct inside-out avian and rodent reaggregate models can assist and di- laminar arrangement, but delays further differentiation, rect progress of human organoid research. In contrast while additional supplementation with RPECM is able to to avian retinal spheroids, however, in rodent (or any drive further differentiation within spheres. Thus, both other mammalian) models a complete laminar retinal components together are important synergistic regu- organisation had never been achieved [1,11,12]. Here, lators to achieve a nearly complete tissue organization we have man-aged to produce highly laminar retinal of a rodent retina in vitro. How these findings can be spheroids from the neonatal Gerbil (Mongolian rat, instrumental in producing human retinal tissues from or Meriones unguiculatus). In a previously established stem cells is briefly discussed. reaggregate model of retinal cells from the perinatal Materials and Methods Gerbil [1], a first sign of histotypical organization was a circular arrangement of calretinin+ amacrine cells, Animals which had directed their processes into internal fibrous Wildtype mongolian Gerbils (Meriones unguiculatus) spaces, thus representing IPL-like areas (IPL: inner plexi- were used throughout this study. Animal handling was form layer). Under the influence of supernatants from performed according to approved national guidelines the RPE (RPE ), these “ipl spaces” began to fuse into a CM and the ARVO statement for animal care. laminar ring below the surface of the sphere. The spher- oids eventually reached a more coherent level of tissue Retinal cell cultures organization, where most cell types were nicely ar- At least 14 retinae from newborn Gerbils (postnatal ranged in cell layers, however, their inside-out orienta- tion was inverted. Noticeably, photoreceptors (PRs) did day 1; P1) were collected under sterile conditions in a not differentiate. Thus, the degree of self-organisation hood. After decapitation, the eyes were isolated gently was remarkable, however, in contrast to the embryonic and collected in cold (4 °C) F-12 medium. The eye cups were opened by a micro-scissor along the ora serrata. avian retina, RPECM alone was not capable of inducing a correct inside-out laminar order, and thus induce the Cornea, lens and vitreous body were removed. The eye reconstruction of an almost complete in vitro retina. cup was turned inside-out and each retina was careful- Therefore, other factors and pathways
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